Retroviruses have played a central role in the elucidation of the mechanisms directing normal cell proliferation and oncogenesis. Recently, we have identified novel cyclin homologs encoded by three retroviruses, walleye dermal sarcoma virus (WDSV) and walleye epidermal hyperplasia viruses 1 and 2 (WEHV1 and WEHV2). These viruses are associated with skin tumors or hyperplasias of fish that appear and regress on a seasonal basis and are the only complex retroviruses to encode oncogenes thus representing a novel paradigm of retroviral-mediated oncogenesis. We are uniquely poised to investigate the molecular mechanisms by which these retroviral cyclins (rv-cyclins) stimulate cell growth and to use these data to investigate the roles of cellular cyclins in normal cell proliferation. This proposal will focus on the biological role(s) of the retroviral cyclins (rv-cyclins) in tumorigenesis and tumor regression. The specific aims of this proposal are: (1) To assess the role of rv-cyclin interaction with cellular protein TRIP-Br1 in cellular proliferation. Many cellular proteins interact with cyclins to regulate cell proliferation and gene expression. We have identified TRIP-Br1, a protein with multiple regulatory roles, as a binding partner of the rv-cyclins. We will analyze the effects of this interaction on cell proliferation and (2) To assess the ability of the WEHV rv-cyclins to stimulate skin cell proliferation in transgenic mice. The sequences of the three rv-cyclin proteins are very diverse and they behave differently in experimental systems. These data suggest that they may have differing abilities to stimulate cell proliferation, analogous to cyclins D1, D2, and D3. We will construct and analyze transgenic mice expressing the rv-cyclins to answer this question. Additionally, we will analyze the expression patterns of proteins that likely mediate cell proliferation in transgenic tissues. [unreadable] [unreadable] [unreadable]